Test method development for mass flow identification of occluding small particulates in microlumens

ABSTRACT

Method and systems for determining acceptance criteria for identification of occluding particles in a lumen of a device are provided. The methods and systems can be used in methods of identifying an occluded device in an inspection method.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/852,498 filed May 24, 2019, the entire disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure provides methods and systems for determiningacceptance criteria for identification of occluding particles in a lumenof a device.

BACKGROUND OF THE INVENTION

The risk of patient injury induced by excessive loads of injectedparticles during hospital stays has long been understood, and reducingtheir occurrence is a primary goal of manufacturers and practitionersalike. A contributing factor to these complications results frompotentially embolic particulates either on, in, or created by, a device,fluid, or other object introduced into the patient. The consequences ofparticles delivered into the bloodstream have long been understood. Withan elementary understanding of anatomy, concern arises that devicesplaced within cardiac chambers could release potentially embolicparticulates. Those discharged into the right side of the heart couldocclude pulmonary arterioles (average diameter <300 micron) if largeenough, potentially resulting in a pulmonary embolism (PE). Left-sidedstudies could direct emboli to the brain, potentially resulting in aCVA. Occlusion of penetrating arterioles (average diameter <100 micron)is of greatest concern, inducing more traumatic neuropathy. While theoccurrence of these events is highly unlikely (<0.2% of procedures), andnot conclusively attributable to the devices used during a study,73907275.1 preventing them further has led to increased scrutiny of themanufacture of anything intended to be positioned in a patient.

Therefore, there is a need for testing methods and systems capable ofidentifying occluding particles within lumens of medical devices.

SUMMARY OF THE INVENTION

One aspect of the present disclosure encompasses a method of determiningacceptance criteria for identification of an occluding particle in alumen of an inspected device. The method comprises isolating a definednumber of one or more occluding test particles and occluding the lumenof a representative device with the defined number of particles byadhering the particles in the lumen of the representative device. Themethod further comprises obtaining a mass flow measurement for theoccluded representative device and calculating an upper test limit massflow rate for the occluded representative device. The upper test limitmass flow rate is the acceptance criteria, and an inspected device isoccluded if a mass flow measurement for the inspected device is equal toor lower than the acceptance criteria, and the inspected device isunoccluded if the mass flow measurement in the inspected device ishigher than the acceptance criteria.

The lumen of more than one representative device can be occluded. Whenthe lumen of more than one device is occluded, the upper test limit massflow rate is an upper boundary of a probability plot at 95/85 confidenceinterval or higher.

Isolating a defined number of particles can comprise suspendingparticles in a bead solution comprising a surfactant and aqueouspolymeric adhesive and isolating one or more single particles undermagnification into a bead solution. The bead solution can be a bufferedbead solution comprising less than about 0.2% aqueous polymeric adhesiveand less than 0.5% surfactant. Adhering the particles in the lumen ofthe representative device can comprise injecting the particle into thelumen of the representative device followed by drying the lumen. Thelumen can be dried by incubating the device in a recirculating air ovenfor about 48 hours at about 65° C.

Obtaining a mass flow measurement for the representative device cancomprise charging the lumen with air to a predetermined pressure, andmeasuring the flow of air sufficient to maintain the pressure over apreset period of time to obtain the mass flow measurement. The mass flowmeasurement can be obtained using a mass flow measurement instrument.The mass flow measurement instrument can be Sentinel Blackbelt TestSystem from Cincinnati Test Systems (CTS).

The representative device can be occluded with one occluding particle.Further, the representative device can be occluded with a 50 micronsNIST traceable particle size standard polystyrene beads.

In some aspects, the device is the Biosense Webster PentaRay EP catheterand the acceptance criteria is 109.23 sccm. In other aspects, the deviceis Abbott (St. Jude Medical) Advisor HD Grid mapping catheters and theacceptance criteria is 157.32 sccm. In yet other aspects, the the deviceis St. Jude Medical BRK Transseptal Needle having a length of 71 cm, andthe acceptance criteria is 175.8 sccm. In yet other aspects, the deviceis St. Jude Medical BRK Transseptal Needle having a length of 89 cm, andthe acceptance criteria is 161.1 sccm. In additional aspects, the deviceis St. Jude Medical BRK Transseptal Needle having a length of 98 cm, andthe acceptance criteria is 154.3 sccm.

Another aspect of the present disclosure encompasses an inspectionmethod for identification of occluding particles in a lumen of aninspected device. The method comprises determining acceptance criteriafor identification of occluding particles in the lumen of the inspecteddevice. Acceptance criteria can be determined as described above.

Once the acceptance criteria for the device is determined, a mass flowmeasurement is obtained for the inspected device. The mass flowmeasurement of the inspected device is obtained and compared to theacceptance criteria. The mass flow measurement of the inspected devicecan be obtained as described above and, if the mass flow measurement ofthe inspected device is equal to or lower than the test acceptancecriteria determined, the inspected device is rejected as comprising anocclusion. The inspected device is accepted if the measured mass flow ofthe inspected devise is higher than the test acceptance criteria for thedevice.

In another aspect, the present disclosure provides a system fordetermining acceptance criteria for identification of occludingparticles in a lumen of a device. The system comprises a mass flowmeasurement instrument for obtaining a mass flow measurement of arepresentative device. The system further comprises a computer systemhaving at least one processor and associated memory comprisinginstructions for calculating an upper test limit mass flow rate for anoccluded representative device and instructions which, when executed byat least one processor, cause the at least one processor to receive massflow measurement of the occluded devices and calculate an upper testlimit mass flow rate for the occluded devices. The computer system alsooutputs the upper test limit mass flow, wherein the upper test limitmass flow rate is the acceptance criteria, and wherein an inspecteddevice is occluded if a mass flow measurement in the inspected device isequal to or lower than the acceptance criteria, and the inspected deviceis unoccluded if the mass flow measurement in the inspected device ishigher than the acceptance criteria.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a plot showing mass flow readings of a device from theoriginal manufacturer, and reprocessed untreated and sham devicestreated with bead solution only.

FIG. 2 is a graph showing the flow rate in sccm in devices loaded withan increasing number of 50 micron particles.

FIG. 3 depicts a cumulative distribution function (CDF) graph of groupedmass flow readings. Samples were grouped by devices containing less than5, less than 100, and less than 1000 particles. Values displayed are thetest limit parameter at 95/90 for each particular group, approximating108 sccm.

FIG. 4 is a probability distribution plot for flow rates from devicescontaining 5 or fewer particles, and the control devices. The 95/90values are shown, along with the calculated test limit value (109.22sccm; dashed vertical line at 109.22 sccm) incorporating system error of0.5% of full scale (1.24 sccm).

FIG. 5 is a plot showing the sccm of devices containing 5 or fewer, or asingle 50 micron particle, and control devices. Dashed horizontal linerepresents the test acceptance criteria of 109.22 for the device.

FIG. 6 are probability distribution plots of samples containing lessthan than 5 particles prior to (Top), and after (Bottom) adding insystem error. With system error, the test acceptance criteriaapproximates 95/99.8.

FIG. 7. FTIR Analysis of microlumens within the Advisor HD Grid andPentaRay catheters.

FIG. 8. Design characteristics of the Advisor HD Grid (top) and PentaRay(bottom) catheters.

FIG. 9A depicts a summary report for reprocessed (No Particulate)devices.

FIG. 9B depicts a summary report for reprocessed (+Particulate) devices.Occluded devices were inoculated with a single 50 μm bead.

FIG. 9C depicts a summary report for Sham devices. Sham devices wereinoculated with the bead buffer (carrier) solution only.

FIG. 10 depicts an interval plot displaying minimal differences in flowbetween non-occluded OM, Reprocessed, and Sham inoculated devices, but asignificant drop in flow between all of those sample sets and thedevices occluded with a single 50 μm bead.

FIG. 11 depicts the upper boundary of the probability plot at 95/95confidence interval for the devices occluded with a single 50 μm bead is157.32 sccm. It is also noted that the OM devices perform in a similarmanner to reprocessed devices (both without particulates). The shamreadings display no significant impact of the carrier fluid on the flowrate (post incubation).

FIG. 12 depicts an equivalence test showing a significant differencebetween the mean of all occluded samples and the acceptance criteria of157.32 sccm, and also between the mean of all reprocessed (non-occluded)samples and the acceptance criteria.

FIG. 13 depicts a distribution plot, which assumes an infinite sampleset, suggests the 95/95 acceptance criteria of 157.32 sccm approaches95/98.

FIG. 14A depicts a summary report for reprocessed (No Particulate)devices.

FIG. 14B depicts a summary report for reprocessed (+Particulate)devices. Occluded devices were inoculated with a single 50 μm bead.

FIG. 14C depicts a summary report for Sham devices. Sham devices wereinoculated with the bead buffer (carrier) solution only.

FIG. 15 shows the mass flow rates for 71 cm OM and Reprocessed deviceswithout an occluding particulate and reprocessed devices inoculated withan occluding particulate. The +Particulate 95/90 upper test limit (UTL)flow rate is shown, defining the acceptance criteria for 71 cm needles.

FIG. 16 shows mass flow rates for 98 cm original manufacturer (OM)devices without an occluding particulate and reprocessed devicesinoculated with an occluding particulate (+Part). The occluded 95/90 UTLflow rate is shown, defining the acceptance criteria for 98 cm needles.

FIG. 17 is a distribution plot of OM mass flow characterization of the89 cm needle.

FIG. 18 are the mass flow rates for each OM size needle, with calculatedacceptance criteria. For 89 cm needles, the acceptance criterion wasderived from the average difference between OM 71 cm and OM 98 cm dataand respective acceptance criteria.

FIG. 19. Image of test fixture.

FIG. 20. Mass Flow readings for devices challenged with a single 50 umparticle, reprocessed (unchallenged devices), and Sham Control devices(challenged with bead buffer alone). 109.22 sccm was defined as the testacceptance criteria during test method development (Example 1).

FIG. 21. No statistical difference in mass flow readings noted betweenunchallenged reprocessed device and sham control (challenged with beadbuffer only) devices.

FIG. 22. A statistical difference noted in mass flow readings betweenunchallenged reprocessed devices and those challenged with a single 50um particle.

FIG. 23. A probability plot suggests that the acceptance criterion(109.22 sccm) is more conservative than that reported at the 95%/90%Upper Bound (107.66 sccm) for challenged devices. All control andunchallenged samples record mass flow readings higher than theacceptance criterion, while all challenged devices record readings wellbelow the acceptance criterion.

FIG. 24. A probability plot suggests that production devices containinga single 50 um occluding particle will test at a 95%/98.3% confidenceinterval when applying the following acceptance criterion of MassFlow≤109.22 sccm=FAIL.

FIG. 25. Images of an isolated particle prior to testing (top) and flushfluid after testing (bottom).

DETAILED DESCRIPTION

The present disclosure encompasses a method of developing a method forinspecting a device comprising a lumen to determine if the lumen of theinspected device is occluded by one or more occluding particles. Themethod can be used in an in-process method of inspecting a device toaccept or pass the inspected device as unoccluded, or reject theinspected device as occluded. The method is capable of detecting andrejecting an inspected device with lumens containing unacceptable levelsof occluding particles. The method can be used with any device having alumen in any field, including the medical field. A method developedaccording to the present disclosure is capable of identifying a singlesmall occluding particle even within the microlumen of a medical device.Importantly, occluding particles smaller than those deemed clinicallyrelevant can be detected using the instant methods. The ability of atest method to detect occluding particles to that resolution provides aconsiderable safety factor when defining acceptance criteria.

I. Method of Determining Acceptance Criteria

In one aspect, the present disclosure provides a method of determiningacceptance criteria for mass flow identification of occluding particlesin a lumen of a device. The acceptance criteria can then be used toaccept an inspected device as unoccluded, or reject an inspected deviceas occluded, for example during reprocessing of medical devices forre-use. A method of the disclosure can be used to detect as few as asingle occluding particle smaller than a particle deemed clinicallyrelevant in an inspected device with a high level of confidence.

(a) Device

A method of the disclosure can be used to determine acceptance criteriafor any device having a lumen. Non-limiting examples of devices includemedical devices such as catheters and andoscopes, micropumps,microvalves, and microsensors, devices in the biological field such asdevices for analyzing biological materials such as proteins, DNA, cells,embryos, and chemical reagents, devices for cell culture, cellseparation, nucleic acid sequencing, devices in the electronicsindustry, for example in cooling channels in silicon chips.

In some aspects, the device is a medical device having a lumen. Medicaldevices that include lumens, such as catheters and endoscopes, areextensively used to perform an array of minimally invasive procedures.Catheters can be inserted into a body cavity, duct, or vessel.Functionally, they allow drainage, administration of fluids or gases,access by surgical instruments, and also perform a wide variety of othertasks depending on the type of catheter. An endoscope is an illuminatedoptical, typically slender and tubular instrument used to look deep intothe body. Endoscopes use tubes which can be a few millimeters thick orsmaller to transfer illumination in one direction and high-resolutionimages in real time in the other direction, and can include tubing withmicrolumens to also perform some procedure, resulting in minimallyinvasive surgeries. Placement of a catheter into a particular part ofthe body may allow:

-   -   Administration of fluids (i.e., heparinized saline, contrast        dyes) during an electrophysiology, or related, study;    -   Fluid sampling during an electrophysiology, or related, study;    -   Direct blood pressure measurement during an electrophysiology,        or related, study;    -   Angioplasty, angiography, balloon septostomy, balloon        sinuplasty, cardiac, catheter ablation;    -   Draining urine from the urinary bladder as in urinary        catheterization, e.g., the intermittent catheters or Foley        catheter or even when the urethra is damaged as in suprapubic        catheterization;    -   Drainage of urine from the kidney by percutaneous (through the        skin) nephrostomy;    -   Drainage of fluid collections, e.g. an abdominal abscess;    -   Drainage of air from around the lung (pigtail catheter);    -   Administration of intravenous fluids, medication or parenteral        nutrition with a peripheral venous catheter;    -   Direct measurement of blood pressure in an artery or vein;    -   Direct measurement of intracranial pressure;    -   Administration of anaesthetic medication into the epidural        space, the subarachnoid space, or around a major nerve bundle        such as the brachial plexus;    -   Administration of oxygen, volatile anesthetic agents, and other        breathing gases into the lungs using a tracheal tube;    -   Subcutaneous administration of insulin or other medications,        with the use of an infusion set and insulin pump;    -   Administering drugs or fluids into a large-bore catheter        positioned either in a vein near the heart or just inside the        atrium;    -   Measuring pressures in the heart;    -   Inserting fertilized embryos from in vitro fertilization into        the uterus;    -   Providing quick access to the central circulation of premature        infants using an umbilical line;    -   Attaching catheters to various other devices;    -   Hemodialysis using a double or triple lumen, external catheter;    -   Artificial insemination.

Some devices can include multiple lumens each performing a specificfunction. These lumens can serve as inflation ports, fluid-transferchannels, guidewire access points, or even steering lumens, amongothers. As such, devices can have one lumen, or can have multiplelumens. For instance, the device can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 or more lumens. The lumens can be a multi-lumen tube (extruded into asingle tube), or can be separately bundled inside a device.

The diameter of a lumen in a medical device can range from about 0.1 toabout 5 mm. For instance, the diameter of a lumen can range from about0.001″ to about 0.1″, or from about 0.01″ to about 0.05″ internaldiameter.

In some aspects, a medical device can further comprise a needle attachedto tubing comprising the lumen. The gage of the needle can range fromabout 50 ga to about 5 ga, from about 40 ga to about 10 ga, or fromabout 30 ga to about 15 ga.

The length of a lumen of a device can range from about 1 cm to a fewmeters. For instance, the length of a lumen can range from about 5 cm toabout 5 meters, from about 20 cm to about 4 m, from about 50 cm to about2 m. In some aspects, the length of a lumen can range from about 50 cmto about 150 cm.

In some aspects, the medical device is selected from a Biosense WebsterPentaRay, an Abbott Advisor HD Grid, an Abbot BRK Transseptal Needle, aBaylis NRG Transseptal Needle, a Boston Scientific Orion; an AbbottResponse with Lumen; a Baylis EPstar; a Phillips Eagle Eye, or an AcutusAcQSpan.

(b) Occluding the Lumen

The method comprises isolating a defined number of one or more occludingtest particles and occluding the lumen of a representative device byadhering the one or more particles in the lumen of the representativedevice. A defined number of particles is an accurate number of isolatedparticles that can vary depending on the acceptance criteria to bedetermined for a device. For instance, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000 or more particles can beisolated for adhering in the lumen of a representative device. In someaspects, a single particle is isolated.

Any method capable of isolating an accurate number of particles can beused in the method, provided the method can isolate a precise number ofparticles. For instance, the number of particles can be isolated bydiluting a solution comprising the one or more particle, and aliquotinga volume of the solution statistically calculated to comprise thedesired number of particles. The number of particles can further beconfirmed in each aliquot, for instance, under magnification. In someaspects, the beads are suspended in a bead solution and isolated undermagnification. The volume of solution into which particles areresuspended can and will vary depending on the device, the size of thelumen of the device, and the number of particles suspended in the beadsolution, among other variables. In some aspects, one or more singleparticles are isolated under magnification into 100 μl of bead solution.In some aspects, the bead solution comprises a surfactant and anadhesive. Surfactants can be as described in Section I(B), and adhesivescan be as described in Section I(C).

The bead solution can comprise about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%,0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or about 5% adhesive. Thebead solution can comprise less than about 0.001%, 0.0055%, 0.01%,0.05%, 0.1%, 0.5%, 1%, 1.5%, or less than about 2% adhesive. In someaspects, the bead solution comprises less than about 0.01%, 0.05%, 0.1%,0.5%, or less than about 1% adhesive. In some aspects, the bead solutioncomprises less than about 0.1%, 0.2%, or less than about 0.3% adhesive.In some aspects, the polymeric adhesive is a polymeric adhesive. In someaspects, the adhesive is a polymeric adhesive, and the solutioncomprises less than about 0.1%, 0.2%, or less than about 0.3% polymericadhesive. In one aspect, the polymeric adhesive is an aqueous polymericadhesive. In some aspects, the adhesive is an aqueous polymericadhesive, and the solution comprises less than about 0.3%, 0.2%, or lessthan about 0.1% aqueous polymeric adhesive.

The bead solution can comprise about 00.01%, 0.05%, 0.1%, 0.5%, 1%,1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, or less thanabout 10% surfactant. The bead solution can comprise less than about0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, or less than about 3% surfactant.In some aspects, the bead solution comprises less than about 00.01%,0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%,8%, 9%, or less than about 10% surfactant. The bead solution cancomprise less than about 00.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, or lessthan about 3% surfactant. In some aspects, the bead solution comprisesless than about 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, or less thanabout 3% surfactant. In some aspects, the bead solution comprises lessthan about 0.3%, 0.2%, or less than about 0.1% surfactant.

In some aspects, the bead solution is a buffered bead solutioncomprising less than about 0.2% aqueous polymeric adhesive and less than0.5% surfactant. Buffered solutions comprise a buffering agent or a pHmodifying agent. Methods of identifying buffering agents to prepare abuffered solution suitable for a bead buffer solution are known in theart and can be determined experimentally. Representative examples ofsuitable buffering agents include, but are not limited to, phosphates,carbonates, citrates, tris buffers, and buffered saline salts (e.g.,Tris buffered saline or phosphate buffered saline). The excipient mayalso be salts for varying osmolarity. By way of non-limiting example,the pH modifying agent may be sodium carbonate, sodium bicarbonate,sodium citrate, citric acid, or phosphoric acid.

The lumen of the representative device is occluded with the definednumber of one or more of the isolated particles. To occlude the lumen,the particles are introduced into the lumen of the representative deviceand adhered in the lumen. Generally, particles are suspended in asolution comprising an adhesive for attaching particles in the lumen andintroduced into the lumen of the representative device. The particlescan be allowed to flow toward the middle of the lumen. The solution canthen be removed and dried of any residual moisture to remove all fluidto not hinder data collection. The solution can be removed by allowingthe solution to evaporate. In some aspects, the solution is ovenincubated to remove residual moisture that could confound the data. Anoven can be a recirculating air oven. In some aspects, the lumen isdried by incubating the device in a recirculating air oven for about 48hours at about 65° C.

An inspection method developed using a method of the disclosure candetect particles as small as 50 microns. The method can also detect awide range of particle quantities, allowing a full scale to be developedby which occlusions (partial or otherwise) could be graded. Forinstance, an inspection method can be developed to select unoccludedinspected devices, or inspected devices occluded to a level acceptablefor the specific device. In some aspects, the representative device isoccluded with one occluding particle. In one aspect, the representativedevice is occluded with 50 microns NIST traceable particle size standardpolystyrene beads

A. Particles

The size of particles suitable for use in the instant disclosure can andwill vary depending on the device, the size of the lumen of the device,the method in which the device is intended for use, and the desiredlevel of resolution of the testing method. In general, particles have anaccurate validated size distribution and shape. Particle size standardsmay be used to validate sizing instruments across their dynamic ranges.They are suitable for use in the performance of routine instrumentcalibration checks and corrections, and in the support of practicestandards, such as those published by ISO, ASTM International, CEN, NISTand other organizations. Additionally, the use of reference materialpermits the standardization of results between runs, instruments andlaboratories, and over time. In some aspects, the particles are NIST(National Institute of Standards and Technology) Traceable SizeStandards. NIST traceability provides an official, objective third-partycomparison of beads to a known standard and maintained by the NationalInstitute of Standards and Technology. The particles can be made of anysuitable material, including polystyrene, silica, and glass.

When the device is a medical device, the particle can have a diameterranging from about 40 nm to 1 μm, from about 1 mm to about 10 μm, orfrom about 200 μm to about 20 μm. In some aspects, the diameter ofparticles suitable for use in the disclosure can have a diameter ofabout 50 μm. In some aspects, the beads are 50 microns NIST traceableparticle size standard polystyrene beads.

B. Surfactants

Surfactants can be included in a bead buffer solution to facilitateintroduction into a lumen and prevent agglomeration of the particles.The solution can comprise one surfactant or a system of surfactantscomprising one or more surfactants.

A variety of surfactants may be included in the surfactant system.Non-limiting examples of suitable nonionic surfactants include sorbitanesters such as sorbitan (Span 20), sorbitan monopalmitate (Span 40),sorbitan monostearate (Span 60), sorbitan monooleate (Span 80), sorbitansesquioleate (Span 83), sorbitan trioleate (Span 85), sorbitanisostearate (Span 120), or combinations thereof; polyethoxylatedsorbitan esters such as polyoxyethylene (20) sorbitan monolaurate (Tween20), polyoxyethylene (4) sorbitan monolaurate (Tween 21),polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene(20) sorbitan monostearate (Tween 60), polyoxyethylene (4) sorbitanmonostearate (Tween 61), polyoxyethylene (20) sorbitan tristearate(Tween 65), polyoxyethylene (20) sorbitan monooleate (Tween 80), orcombinations thereof; polyglycerol esters of fatty acids such astriglycerol monolaurate, triglycerol monooleate, triglycerolmonostearate, polyglycerol oleate, polyglycerol, laurate, polyglycerolstearate, polyglycerol polyricinoleate, and so forth; and other nonionicsurfactants such as glyceryl monolaurate, glyceryl monooleate, glycerylmonostearate, glycol distearate, glycol stearate, ceteareth-20, cetearylglycoside, ceteth-2, ceteth-10, ceteth-20, cocamide MEA, isoceteth-20,isosteareth-20, laureth-4, laureth-23, methyl glucose sesquistearate,oleth-2, oleth-10, oleth-20, PEG-100 stearate, PEG-20 almond glycerides,PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-7hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-35hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60hydrogenated castor oil, PEG-200 hydrogenated glyceryl palmate, PEG-30dipolyhydroxystearate, PEG-4 dilaurate, PEG-40 sorbitan peroleate, PEG-7olivate, PEG-7 glyceryl cocoate, PEG-8 dioleate, PEG-8 laurate, PEG-8oleate, PEG-80 sorbitan laurate, PEG-40 stearate, propylene glycolisostearate, stearamide MEA, steareth-2, steareth-20, steareth-21,steareth-100, polyoxyethylene (7-8) p-t-octyl phenol (Triton X-114),polyoxyethylene (9-10) p-t-octyl phenol (Triton X-100), polyoxyethylene(9-10) nonylphenol (Triton N-101), polyoxyethylene (9) p-t-octyl phenol(Nonidet P-40), polyoxyethylene (10) cetyl ether (Brij 56),polyoxyethylene (20) cetyl ether (Brij 58), polyoxyethyleneglycoldodecyl ether (Brij 35), copolymers of ethylene oxide and propyleneoxide (e.g., Pluronic F-68, Pluronic F-127, etc.),dimethyldecylphosphine oxide (APO-10), dimethyldodecylphosphine oxide(APO-12), cyclohexyl-n-ethyl-β-D-maltoside,cyclohexyl-n-hexyl-β-D-maltoside, cyclohexyl-n-methyl-β-maltoside,n-decanoylsucrose, n-decyl-β-D-glucopyranoside,n-decyl-β-maltopyranoside, n-decyl-β-D-thiomaltoside, n-dodecanoylsucrose, decaethylene glycol monododecyl ether,N-decanoyl-N-methylglucamine, n-decyl α-D-glucopyranoside, decylβ-D-maltopyranoside, n-dodecanoyl-N-methylglucamide, n-dodecylα-D-maltoside, n-dodecyl β-D-maltoside, heptane-1,2,3-triol,heptaethylene glycol monodecyl ether, heptaethylene glycol monododecylether, heptaethylene glycol monotetradecyl ether, n-hexadecylβ-D-maltoside, hexaethylene glycol monododecyl ether, hexaethyleneglycol monohexadecyl ether, hexaethylene glycol monooctadecyl ether,hexaethylene glycol monotetradecyl ether,methyl-6-O—(N-heptylcarbamoyl)-α-D-glucopyranoside, nonaethylene glycolmonododecyl ether, N-nonanoyl-N-methylglucamine,N-nonanoyl-N-methylglucamine, octaethylene glycol monodecyl ether,octaethylene glycol monododecyl ether, octaethylene glycol monohexadecylether, octaethylene glycol monooctadecyl ether, octaethylene glycolmonotetradecyl ether, octyl-β-glucoside, octyl-β-thioglucoside,octyl-β-D-glucopyranoside, octyl-β-D-1-thioglucopyranoside,pentaethylene glycol monodecyl ether, pentaethylene glycol monododecylether, pentaethylene glycol monohexadecyl ether, pentaethylene glycolmonohexyl ether, pentaethylene glycol monooctadecyl ether, pentaethyleneglycol monooctyl ether, polyethylene glycol diglycidyl ether,polyethylene glycol ether, polyoxyethylene (10) tridecyl ether,polyoxyethylene (100) stearate, polyoxyethylene (20) isohexadecyl ether,polyoxyethylene (20) oleyl ether, polyoxyethylene (40) stearate,polyoxyethylene (50) stearate, polyoxyethylene (8) stearate,polyoxyethylene bis(imidazolyl carbonyl), polyoxyethylene (25) propyleneglycol stearate, saponin from Quillaja bark, tetradecyl-β-D-maltoside,tetraethylene glycol monodecyl ether, tetraethylene glycol monododecylether, tetraethylene glycol monotetradecyl ether, triethylene glycolmonodecyl ether, triethylene glycol monododecyl ether, triethyleneglycol monohexadecyl ether, triethylene glycol monooctyl ether,triethylene glycol monotetradecyl ether, tyloxapol, n-undecylβ-D-glucopyranoside, octylphenoxypolyethoxyethanol (IGEPAL CA-630),polyoxyethylene (5) nonylphenylether (IGEPAL CO-520), polyoxyethylene(150) dinonylphenyl ether (IGEPAL DM-970), or combinations thereof.

Examples of suitable zwitterionic surfactants include, without limit,lecithins (e.g., a lecithin extracted from soybeans, eggs, milk, marinesources, rapeseed, cottonseed, sunflower, and the like), hydrolyzedlecithins, hydrogenated lecithins, acetylated lecithins,3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate(CHAPSO), 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate(CHAPS),3-(4-heptyl)phenyl-3-hydroxypropyl)dimethylammoniopropanesulfonate(C7BzO), 3-(N,N-dimethyloctylammonio) propanesulfonate inner salt(SB3-8), 3-(decyldimethylammonio) propanesulfonate inner salt (SB3-10),3-(dodecyldimethylammonio) propanesulfonate inner salt (SB3-12),3-(N,N-dimethyltetradecylammonio)propanesulfonate (SB3-14),3-(N,N-dimethylpalmitylammonio) propanesulfonate (SB3-16),3-(N,N-dimethyloctadecylammonio) propanesulfonate (SB3-18),3-[N,N-dimethyl(3-myristoylaminopropyl)ammonio]propanesulfonate(ASB-14), caprylyl sulfobetaine, capric amidopropyl betaine,capryloamidopropyl betaine, cetyl betaine, cocamidopropyl betaine,C12-14 alkyl dimethyl betaine, cocamidopropyl dimethylaminohydroxypropylhydrolyzed collagen, N-[3-cocamido)-propyl]-N,N-dimethyl betaine,cocamidopropyl hydroxysultaine, cocamidopropyl sulfobetaine,cocaminobutyric acid, cocaminopropionic acid, cocoamphodipropionic acid,coco-betaine, cocodimethylammonium-3-sulfopropylbetaine,cocoiminodiglycinate, cocoiminodipropionate, coco/oleamidopropylbetaine, cocoyl sarcosinamide DEA, DEA-cocoamphodipropionate,dihydroxyethyl tallow glycinate, dimethicone propyl PG-betaine,N,N-dimethyl-N-lauric acid-amidopropyl-N-(3-sulfopropyl)-ammoniumbetaine, N,N-dimethyl-N-myristyl-N-(3-sulfopropyl)-ammonium betaine,N,N-dimethyl-N-palmityl-N-(3-sulfopropyl)-ammonium betaine,N,N-dimethyl-N-stearamidopropyl-N-(3-sulfopropyl)-ammonium betaine,N,N-dimethyl-N-stearyl-N-(3-sulfopropyl)-ammonium betaine,N,N-dimethyl-N-tallow-N-(3-sulfopropyl)-ammonium betaine, disodiumcaproamphodiacetate, disodium caproamphodipropionate, disodiumcapryloamphodiacetate, disodium capryloamphodipropionate, disodiumcocoamphodiacetate, disodium cocoamphodipropionate, disodiumisostearoamphodipropionate, disodium laureth-5 carboxyamphodiacetate,disodium lauriminodipropionate, disodium lauroamphodiacetate, disodiumlauroamphodipropionate, disodium octyl b-iminodipropionate, disodiumoleoamphodiacetate, disodium oleoamphodipropionate, disodiumPPG-2-isodeceth-7 carboxyamphodiacetate, disodium stearoamphodiacetate,N,N-distearyl-N-methyl-N-(3-sulfopropyl)-ammonium betaine, ethylhexyldipropionate, ethyl hydroxymethyl oleyl oxazoline, ethyl PEG-15 cocaminesulfate, isostearamidopropyl betaine, lauramidopropyl betaine,lauramidopropyl dimethyl betaine, lauraminopropionic acid,lauroamphodipropionic acid, lauroyl lysine, lauryl betaine, laurylhydroxysultaine, lauryl sultaine; linoleamidopropyl betaine,lysolecithin, myristamidopropyl betaine, octyl dipropionate,octyliminodipropionate, oleamidopropyl betaine, oleyl betaine,4,4(5H)-oxazoledimethanol, palmitamidopropyl betaine, palmitamine oxide,ricinoleamidopropyl betaine, ricinoleamidopropyl betaine/IPDI copolymer,sesamidopropyl betaine, sodium C12-15 alkoxypropyl iminodipropionate,sodium caproamphoacetate, sodium capryloamphoacetate, sodiumcapryloamphohydroxypropyl sulfonate, sodium capryloamphopropionate,sodium cocaminopropionate, sodium cocoamphoacetate, sodiumcocoamphohydroxypropyl sulfonate, sodium cocoamphopropionate, sodiumdicarboxyethyl cocophosphoethyl imidazoline, sodiumisostearoamphopropionate, sodium lauriminodipropionate, sodiumlauroamphoacetate, sodium oleoamphohydroxypropylsulfonate, sodiumoleoamphopropionate, sodium stearoamphoacetate, sodiumtallamphopropionate, soyamidopropyl betaine, stearyl betaine, trisodiumlauroampho PG-acetate phosphate chloride, undecylenamidopropyl betaine,or combinations thereof.

In some aspects, the surfactant is Triton™ X-100, Tween® 20, orcombinations thereof.

C. Adhesive

The particles are adhered in the lumen using an aqueous polymericadhesive. In some aspects, a suitable adhesive is a polymeric adhesive.Non-limiting examples of suitable polymeric glues include epoxy resins,epoxy putty, ethylene-vinyl acetate (a hot-melt glue), phenolformaldehyde resin, polyamide, polyester resins, polyethylene (ahot-melt glue), polypropylene, polysulfides, polyurethane, polyvinylacetate (PVA), polyvinyl alcohol, polyvinyl chloride (PVC), polyvinylchloride emulsion (PVCE), polyvinylpyrrolidone (PVP), rubber cement,silicones, silyl modified polymers, and styrene acrylic copolymer. Acombination of more than one glue can also be used in a bead solution.In some aspects, the adhesive is a water-based adhesive such as PVP. Itwill be recognized that the concentration of the glue in a bead solutioncan and will vary depending on the glue, the particle material, andmaterial of the lumen. However, any concentration of glue sufficient toadhere and maintain the particles in the lumen can be used, and can bedetermined experimentally.

(c) Mass Flow Measurement

The method comprises obtaining a mass flow measurement for arepresentative device occluded as described in Section I(b). During massflow measurement, a lumen can be charged to a predetermined pressurewith air, and then air can be delivered through the lumen at asufficient rate to maintain that pressure, thereby obtaining the massflow rate. The mass flow rate can be the standard cubic centimers perminute (sccm). One sccm indicates the mass flow rate of one cubiccentimeter per minute of a fluid.

Impacted by the cross-sectional area of the blockage, a fully occludeddevice will allow little to no quantity (ΔAQ=0) of gas to exit thelumen, thereby requiring little to no additional flow of air to maintainthe charge pressure. Non-occluded devices will allow full and rapid flowof gas exiting the lumen, as there is no impedance other than thatprovided by the properties of the lumen itself (i.e., material,geometry, surface finish, etc.). This will require a much higher flow ofair to maintain the charge pressure. Partially occluded devices willimpede this flow to the degree by which they are obstructed as definedin the standard mass flow equation below, requiring a flow of airbetween that of the fully and non-occluded devices.

${\Delta Q} = \frac{{\pi\Delta}\;{Pd}^{4}}{128\mspace{14mu}\mu\; l}$

As such, any mass flow measurement instrument can be used in thismethod, provided the device can accommodate a device of interest, andprovide the desired pressure. For instance, the mass flow measuringdevice is able to accommodate a device comprising a lumen having thecorrect lumen size, and capable of providing an unimpeded flow rate ofany subject device sufficient for the development of an inspectionmethod. When the device is a medical device comprising a microlumen, themass flow measurement instrument can be the Sentinel Blackbelt TestSystem from Cincinnati Test Systems (CTS).

It will be understood that flow characteristics differ between differenttypes of devices, and can be affected by, among other variables, thematerial in the lumen, lumen diameter and architecture, usable length,curves or device-specific parts attached along the fluid flow of thelumen. Therefore, characterization of each device is required in thedevelopment of device-specific test acceptance criteria. The mass flowrate for each device can be determined experimentally by measuring themass flow through an unoccluded device. Similarly, a predeterminedpressure to which a lumen is charged, and a preset period of time forwhich the flow of air is maintained also depend on the device, the lumenof the device, and the mass flow measuring device among other variables,and can be determined experimentally.

(d) Calculating a Test Limit Value

The method comprises calculating an upper test limit mass flow rate fora device of interest. An upper test limit mass flow rate can be theupper boundary of a probability plot at 95/85 confidence interval orhigher. For instance, upper test limit mass flow rate can be the upperboundary of a probability plot at a confidence interval of 95/85, 95/85,95/85, 95/85, 95/85, 95/90, 95/90, 95/90, 95/90, 95/90, 95/90, 95/90,95/90, 95/90, 95/90 or above. In some aspects, the test limit can beabout 95/99.82.

In some aspects, the upper test limit value is calculated by preparing aprobability distribution plot for flow rates from more than onerepresentative device occluded with a defined number of particles. Theupper test limit mass flow rate is the acceptance criteria, and aninspected device is occluded if a mass flow measurement in the inspecteddevice is equal to or lower than the acceptance criteria, and aninspected device is unoccluded if the mass flow measurement in theinspected device is higher than the acceptance criteria.

In example 1, a probability distribution plot for flow rates fromBiosense Webster PentaRay EP catheters containing 5 or fewer particlesand from control catheters is shown in FIG. 4. The upper test limitvalue at 95/90 confidence interval for the PentaRay catheter wascalculated to be 109.22 sccm, and is shown in FIG. 4 as a dashedvertical line. In some aspects, the device is Biosense Webster PentaRayEP catheter, and the acceptance criteria is 109.23 sccm. In otheraspects, the device is Abbott (St. Jude Medical) Advisor HD Grid mappingcatheters, and the acceptance criteria is 157.32 sccm. In yet otheraspects, the device is St. Jude Medical BRK Transseptal Needle having alength of 71 cm, and the acceptance criteria is 175.8 sccm. In otheraspects, the device is St. Jude Medical BRK Transseptal Needle having alength of 89 cm, and the acceptance criteria is 161.1 sccm. Inadditional aspects, the device is St. Jude Medical BRK TransseptalNeedle having a length of 98 cm, and the acceptance criteria is 154.3sccm. In other aspects, the device is St. Jude Medical BRK TransseptalNeedle having a length of 89 cm, and the acceptance criteria is 161.1sccm.

As explained above in Section I(c), flow rate is device-specific.Therefore, an upper test limit mass flow rate can be determined for eachtype of device.

II. Inspection Methods

In one aspect, the present disclosure provides an inspection method foridentification of occluding particles in a lumen of an inspected device.The method comprises determining acceptance criteria for identificationof occluding particles in the lumen of the inspected device. Acceptancecriteria can be determined as described in Section I above.

Once the acceptance criteria for the device is determined, a mass flowmeasurement is obtained for an inspected device. The mass flowmeasurement of the inspected device is obtained and compared to theacceptance criteria. The mass flow measurement of the inspected devicecan be obtained as described in Section I(b) and, if the mass flowmeasurement of the inspected device is equal to or lower than the testacceptance criteria determined, the inspected device is rejected ascomprising an occlusion. The inspected device is accepted if themeasured mass flow of the inspected devise is higher than the testacceptance criteria for the device.

III. Computer-Implemented Methods and Systems

In one aspect, the present disclosure provides a system foridentification of an occluding particle in an inspected device. Thesystem comprises a mass flow measurement instrument for obtaining a massflow measurement for the inspected device. The system also comprises acomputer system having at least one processor and associated memorycomprising acceptance criteria for identification of occluding particlesin a lumen of the inspected device and instructions which, when executedby the at least one processor, cause the at least one processor toreceive the mass flow measurement and compare the mass flow measurementfor the inspected device to the acceptance criteria. The processor alsooutputs inspection results for identifying an occluded inspected device,wherein the inspected device is occluded if a mass flow measurement inthe inspected device is equal to or lower than the acceptance criteria,and the inspected device is unoccluded if the mass flow measurement inthe inspected device is higher than the acceptance criteria.

In another aspect, the present disclosure provides a system fordetermining acceptance criteria for identification of occludingparticles in a lumen of a device. The system comprises a mass flowmeasurement instrument for obtaining a mass flow measurement of arepresentative device. The system further comprises a computer systemhaving at least one processor and associated memory comprisinginstructions for calculating an upper test limit mass flow rate for anoccluded representative device and instructions which, when executed byat least one processor, cause the at least one processor to receive massflow measurement of the occluded devices and calculate an upper testlimit mass flow rate for the occluded devices. The computer system alsooutputs the upper test limit mass flow, wherein the upper test limitmass flow rate is the acceptance criteria, and wherein an inspecteddevice is occluded if a mass flow measurement in the inspected device isequal to or lower than the acceptance criteria, and the inspected deviceis unoccluded if the mass flow measurement in the inspected device ishigher than the acceptance criteria.

In one aspect, the present disclosure provides at least onenon-transitory computer readable medium storing instructions which, whenexecuted by at least one processor, cause the at least one processor toreceive a mass flow measurement of occluded devices and calculate anupper test limit mass flow rate for the occluded devices. Theinstructions also cause the at least one processor to output testresults for accepting or rejecting an inspected device, wherein aninspected device is occluded if the mass flow measurement in theinspected device is equal to or lower than the acceptance criteria, andthe inspected device is unoccluded if the mass flow measurement in theinspected device is higher than the acceptance criteria.

In yet another aspect, the present disclosure provides at least onenon-transitory computer readable medium storing instructions which, whenexecuted by the at least one processor, cause the at least one processorto receive a mass flow measurement of an inspected device and comparethe mass flow measurement for the inspected device to the acceptancecriteria. The instructions also cause the at least one processor tooutput test results for accepting or rejecting the device, wherein aninspected device is occluded if the mass flow measurement in theinspected device is equal to or lower than the acceptance criteria, andthe inspected device is unoccluded if the mass flow measurement in theinspected device is higher than the acceptance criteria.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references provide one ofskill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2nd ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, TheHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms have the meanings ascribed to them unless specifiedotherwise.

When introducing elements of the present disclosure or the preferredaspects(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

Methods according to the above can be implemented usingcomputer-executable instructions that are stored or otherwise availablefrom computer-readable media. Such instructions can comprise, forexample, instructions and data which cause or otherwise configure ageneral purpose computer, special purpose computer, or special purposeprocessing device to perform a certain function or group of functions.Portions of computer resources used can be accessible over a network.The computer executable instructions may be, for example, binaries,intermediate format instructions such as assembly language, firmware, orsource code. Examples of computer-readable media that may be used tostore instructions, information used, and/or information created duringmethods according to described examples include magnetic or opticaldisks, flash memory, USB devices provided with non-volatile memory,networked storage devices, and so on.

Devices implementing methods according to these disclosures can comprisehardware, firmware and/or software, and can take any of a variety ofform factors. Typical examples of such form factors include laptops,smart phones, small form factor personal computers, personal digitalassistants, rackmount devices, standalone devices, and so on.Functionality described herein also can be embodied in peripherals oradd-in cards. Such functionality can also be implemented on a circuitboard among different chips or different processes executing in a singledevice, by way of further example.

The instructions, media for conveying such instructions, computingresources for executing them, and other structures for supporting suchcomputing resources are means for providing the functions described inthese disclosures.

As various changes could be made in the above-described methods withoutdeparting from the scope of the invention, it is intended that allmatter contained in the above description and in the examples givenbelow, shall be interpreted as illustrative and not in a limiting sense.

As used herein, the term “clinically relevant” refers to a level ofparticles that may be capable of increasing patient embolic risk.

As used herein, the term “occluded device” refers to a device comprisinga lumen and having a lumen occluded by one or more occluding particles.

As used herein, the term “unoccluded device” refers to a devicecomprising a lumen and having a lumen clear of any occluding particles.

As used herein, the term “representative device” refers to a device usedto determine acceptance criteria for an inspected device.

As used herein, an “inspected device” refers to a device havingundergone a mass flow measurement for use in a method or system foridentifying occluding particles in the lumen of the device.

As used herein, the term “device,” when not qualified by the terms“inspected” or “representative”, refers to the device for whichacceptance criteria are developed, and which undergoes testing foridentification of occluding particles in a lumen of the device.

EXAMPLES

All patents and publications mentioned in the specification areindicative of the levels of those skilled in the art to which thepresent disclosure pertains. All patents and publications are hereinincorporated by reference to the same extent as if each individualpublication was specifically and individually indicated to beincorporated by reference.

The publications discussed throughout are provided solely for theirdisclosure before the filing date of the present application. Nothingherein is to be construed as an admission that the invention is notentitled to antedate such disclosure by virtue of prior invention.

The following examples are included to demonstrate the disclosure. Itshould be appreciated by those of skill in the art that the techniquesdisclosed in the following examples represent techniques discovered bythe inventors to function well in the practice of the disclosure. Thoseof skill in the art should, however, in light of the present disclosure,appreciate that many changes could be made in the disclosure and stillobtain a like or similar result without departing from the spirit andscope of the disclosure, therefore all matter set forth is to beinterpreted as illustrative and not in a limiting sense.

Example 1. Development of Mass Flow Method of Identification ofOccluding Particles in Microlumens

An in-process inspection testing method capable of detecting andrejecting devices with microlumens containing unacceptable levels ofclinically relevant particles is presented herein.

By adapting current leak testing technology, validated for use in nearlyevery field, including medical, we have developed a mass flow inspectiontest that is capable of identifying a single small particle within amicrolumen. Further, our investigation also showed that this methodcould repeatedly identify a wide range of particle quantities, allowinga full scale to be developed by which occlusions (partial or otherwise)could be graded. This test method is intended to create a new standardby which manufacturers of medical devices containing small lumens shouldconsider when attempting to mitigate periprocedural patient risk.

Introduction.

Performed to diagnose and treat most arrythmias, an EP study utilizesspecialized catheters, introducers, and other complex technologies.These devices are most often inserted via venous (femoral) access anddelivered to the right atrium, with a transseptal puncture providingaccess to left-sided anatomy as necessary. Most studies are routine,completed in a few hours, and the patient can be expected to resumenormal daily activities within just a few days. However, with anelementary understanding of anatomy, concern arises that devices placedwithin cardiac chambers could release potentially embolic particulates.Those discharged into the right side of the heart could occludepulmonary arterioles (average diameter <300 micron) if large enough,potentially resulting in a pulmonary embolism (PE). Left-sided studiescould direct emboli to the brain, potentially resulting in a CVA.Occlusion of penetrating arterioles (average diameter <100 micron) is ofgreatest concern, inducing more traumatic neuropathy.

A contributing factor to these complications results from potentiallyembolic particulates either on, in, or created by, a device, fluid, orother object introduced into the patient. The consequences of particlesdelivered into the bloodstream have long been understood. But, whilecatheters have been used for EP studies for decades, there exists nosingle, well-defined standard for particulates on or in an EP catheter,or related, by which manufacturers of such devices must adhere. Manydefault to those drafted by the United States Pharmacopeia (USP),particularly the direction found in General Chapter <1> Injections andImplanted Drug Products. This chapter focuses on parenternal drugproducts that are injected or implanted into the body. It further pointsto other chapters that define additional testing requirements unique tothe many different materials considered. The chapter commonly referencedby catheter manufacturers when discussing particulate acceptancecriteria is <788> Particulate Matter in Injections. This chapter definesacceptable particulate sizes and quantities in injectables, and the testmethods used to characterize them. Here, acceptance criteria focus onlarger amounts (600 or 6000) of smaller particulates (25 or 10 micron,respectively). The clinical concern is that patients often receivemultiple injections of various required solutions during their care. Ithas been estimated that a patient in intensive care is injected with asmany as a million particles larger than 2 micron every day of theirstay. While lesser amounts of smaller particles may not be acutelytraumatic, cumulative doses of smaller particulates has provendeleterious. For example, parenternal nutrition solutions have beenshown in the past to include nearly 40,000 particles upwards of 100micron each in daily feedings, with little to no acute risk. However,prolonged administration allows for the accumulation of fatal quantitiesof particles. Because of this, minimizing the quantity of smallerparticles in each injection, either via implementation of inline filtersand/or improved manufacturing techniques, will reduce the overall load apatient experiences, abating risk of further embolic complication.

Additional governance is provided by USP regarding perfusionscintigraphy studies, recommending the majority of particulates involvedbe around 90 micron in diameter (ranging from 20-150 micron), with nonelarger than 150 micron. It has been shown that smaller particles (<40micron) may pass through the vasculature of interest and travel to, andbecome lodged in, unintended sites potentially leading to delayeddisfunction after a critical load has been administered, while largerparticles (>200 micron) may block arteries and arterioles, resulting inacute focal defects.

Both the Association for the Advancement of Medical Instrumentation(AAMI) and the Food and Drug Administration have released severalguiding documents, such as TIR42 (AAMI) and “Guidance for Coronary,Peripheral, and Neurovascular Guidewires” (FDA), among others. These aresimilar to USP<788> in that they recommend the characterization ofcertain sizes of particulates that may originate from the medicaldevices each is focused on, but stop short of defining quantity and sizeacceptance criteria. This is mostly due to the fact that there is anunderstandable lack of research involving human subjects given theethical concerns involved. These documents instead rely on the manyrelated studies employing animal models. While direct correlation isconfounded by differences in anatomy, basic principles apply and areintended to aid each manufacturer in defining their own acceptancecriteria.

In addition to device-attributed particulates discharged into thevasculature, there is also a concern about potentially embolic-freecirculating particulates created during an EP study, especially thoseprocedures involving ablation of intracardiac surfaces. Several studieshave identified asymptomatic cerebral lesions via MRI following ablationprocedures, leading to a presumed direct correlation between ablationprocedures and the production of emboli. A recent pair of studies,sponsored by Medtronic, considered the effect of microembolic materials(either air bubbles or pulverized dried blood) created during ablationin the left atrial chamber on canine and porcine models.

The first study investigated the production of microbubbles and embolicparticulates during pulmonary vein (PV) ablation in porcine subjectsusing two specific catheters (Biosense Webster and Medtronic). In thisstudy, microbubbles and coagulum (averaging 225-250 micron depending onthe catheter used) were identified and attributed to the use of thedevices, but no evidence of acute cerebral lesions was observed in anyof the six participant animals. 73 micron extracorpeal filters were usedto collect debris, allowing all smaller debris to continue circulation.In two of the animals, renal arterial occlusion was present withsubsequent tubular necrosis, but no other lesions or dysfunction wasreported elsewhere.

In the second study, over 4000 particulates or a quantity ofmicrobubbles were injected into a canine subject in four doses (4injections of >1000 particles, or up to 4 injections of 0.5 mL ofmicrobubbles). Several ranges of sizes were considered, from 75-250micron to 90-600 micron. The effects of introducing single particles ormicrobubbles of any size were not studied. Nor were the effects afterintroducing a quantity of particles of a single size. The location ofthe injection (vertebral vs carotid sinus) and the size of theparticulates directly correlated with increased severity of the outcome.

In both studies, as in several others before and since, a significantload (quantity 10³-10⁶) of larger embolic (>>>50 micron) particles wererequired to cause injury. Studies on atheroemboli to the brain haveshown a remarkable acute tolerance of considerably large emboli (50-300micron) by the cerebral vasculature, likely due to redundant bloodsupplies caused by arterial anastomoses and arteriovenous shunts.Considering the other end of the spectrum, an oft-cited work by Heistad,et al., studied the injection of nearly 30,000 smaller beads (15 micron)into a dog model. He repeated these injections 25 times, observing noill effects or neurologic deficits. However, when he injected a similarquantity of 50 micron beads, altered blood flow was observed after asingle dose. Together, this reinforces the earlier conclusion that fewerlarger particles can be more harmful than an even greater quantity ofsmaller particles, and that multiple (>10³) particles in the arteriolesize range and smaller are required to induce significant injury.

Manufacturers of products used during EP studies have a shared goal toreduce periprocedural patient injury, especially emboli. As such, goodmanufacturing practices include methods that specifically minimizeand/or remove particulates on or in these products. Further, adequateinline inspection should be performed on each device, rejecting thosethat contain an unacceptable level of particulates. This is a relativelyroutine task when patient contacting surfaces are visible on theexterior of the device. Low level magnification allows for detection ofparticles that could be of concern. Unfortunately, this becomessignificantly more complicated with devices that contain lumens,especially when they are inaccessible. Visualization solutions exist formacrolumens, but more specialized testing must be developed andvalidated for other microlumen products. The testing methods that followdiscuss a novel approach to identifying clinically relevant levels ofparticulates within microlumens or EP devices.

Test Method Development

The test to identify occluded devices relies on standard principles offluid dynamics and physics where:

Flow(Q) = Quantity (q) Pressure(P) = Force (F) Time (t) Area (A)

A lumen can be charged to a certain pressure with air, and then air canbe delivered through the lumen at a rate required to maintain thatpressure. Impacted by the cross-sectional area of the blockage, a fullyoccluded device will allow little to no quantity (ΔAQ=0) of gas to exitthe lumen, thereby requiring little to no additional flow of air tomaintain the charge pressure. Non-occluded devices will allow full andrapid flow of gas exiting the lumen, as there is no impedance other thanthat provided by the properties of the lumen itself (i.e., material,geometry, surface finish, etc.). This will require a much higher flow ofair to maintain the charge pressure (FIG. 1). Partially occluded deviceswill impede this flow to the degree by which they are obstructed asdefined in the standard mass flow equation below, requiring a flow ofair between that required for the fully and non-occluded devices.

This testing is commonly referred to as mass flow testing. It is ideallysuited for use with microlumens because it is capable of grading thedegree of blockage, which is necessary for detecting partial occlusionscaused by small particles. Other pressure-based methods are designed fordetecting only higher levels of occlusion, so are poorly suited for thisapplication. The addition of a mass flow transducer along with thepressure sensor provides the added sensitivity necessary to ensure thatonly acceptable levels of particles remain on a device.

The mass flow testing was conducted using a Cincinnati Test Systems(CTS) Sentinel Blackbelt Test System. It utilizes clean, dry,pressurized air to create positive pressure inside a device and providesconstant timed flow, which is then sensed by mass flow transducersaccurate to 0.5% of full scale (248 sccm scale=±1.2 sccm error). Data isdisplayed at a 0.00001 resolution.

Development of this test method involved an assessment of the ability ofto distinguish between different sized particles as well as differentquantities of similar sized particles. This established both asensitivity range and determined if the instrument was capable ofdetecting a particle smaller than that deemed clinically relevant.Developing the method to detect particle smaller than that deemedclinically relevant provides for a safety factor, rejecting devicescontaining such small particles. Based on the review of literature, anddiscussions with the FDA, a particle size of 50 micron was chosen forestablishing acceptance criteria.

The Mass Flow method described herein will be used to establish the testsettings for in-process inspection of microlumen devices using the CTSSentinel Blackbelt test system. The microlumen device used herein is areprocessed Biosense Webster PentaRay EP catheter. Designcharacteristics of the device are shown in FIG. 8.

Methods

To define the parameters of the test method, occlusions were created byinjecting 50 micron NIST traceable particle size standard polystyrenebeads, suspended in bead solution containing ultrapure water, a dilute(<0.2%) aqueous polymeric adhesive and surfactant (<0.5%), into thelumen of each device and allowed to disperse throughout. The surfactantwas included to prevent agglomeration in solution while the adhesive wasused to lightly adhere the beads to the lumen wall following evaporationof the bead solution. Samples were oven incubated, removing residualmoisture that could confound the data.

Control devices included unchallenged original manufacturer devices(OM), unchallenged reprocessed devices (REP), and reprocessed deviceswith bead solution (SHAM) containing no particles.

Solutions were prepared containing either 10⁴,10³, 500, 100, 50, 5, 2,or 1 (per 100 μl solution) 50 micron bead(s). These were injected intothe lumen of three devices per quantity (24 total samples with beads).

All samples were tested 5 times and the flow data recorded in standardcubic centimeters per minute (sccm).

Results

Data was recorded and analyzed in Excel (Microsoft Office 365) andMinitab 18. All statistical analysis was completed in Minitab 18 usingthe Smallest Extreme Distribution where applicable.

Control samples were tested, as shown in FIG. 1. There was nostatistical difference between REP and SHAM devices. The OM devicesperformed over a lower and wider range, suggesting an artifact of themanufacturing process that is removed during reprocessing (or stretchingof the lumen to a uniform diameter following clinical use of pressurizedheparinized saline and subsequent reprocessing).

The average mass flow decreased (blue) as the quantity of particlesincreased, as expected, confirming that additional particles furtherocclude the lumen (FIG. 2). The yellow line reports the average datafrom the control samples, which proved significantly higher than any ofthe challenged devices. The average control device had a mass flowreading of 112.01 sccm, whereas the single particle challenged deviceaveraged 106.68 sccm. This data also confirms that the mass flow test onthe CTS Sentinel Blackbelt, as designed, is capable of detecting asingle 50 micron particle.

A cumulative distribution function (CDF) was calculated from groupedflow rate data. Devices were grouped by those containing less than 1000(N=17 devices), less than 100 (N=12 devices), and less than 5 particles(N=5 devices), and the 95/90 confidence interval test limits are shown,nearing 108 sccm (FIG. 3). The test limit parameter at 95/90 for eachparticular group, approximated 108 sccm. A probability plot focused onthe group of devices containing 5 or fewer particles and compared themto the control devices (FIG. 4). The 95/90 values are shown, with thered line at 109.22 sccm incorporating in system error of 0.5% of fullrange, establishing the suggested test acceptance criteria. It is notedthat this value is above the upper bound at 95/90, providing even moreconfidence to this defined parameter.

As seen in FIG. 5, both the <5 and 1 particle devices provided mass flowreadings that were considerably lower than the 109.22 sccm definedacceptance criteria. In process, this would result in these devicesfailing the lumen inspection test, and being rejected from further use.Applying a Probability Distribution Plot to the <5 micron particle data,the test acceptance criteria of 109.22 (95/90+system error) approximates95/99.82, providing an even greater safety factor and confidence (FIG.6).

Defined test parameters for the Biosense Webster PentaRay EP catheterare shown in Table 1.

Prefill  50% Fill  3.00 s Test  3.00 s Exhaust  0.50 s Relax  5.00 sMinimum Change in Mass Flow (PASS) 109.23 sccm All data above this limitwill pass Maximum Change in Mass Flow (FAIL) 109.22 sccm All data belowthis limit will fail

Conclusion

It is well understood that fewer large (»200 micron) particles arerequired to create a similar embolic injury as smaller particles (<100micron). However, the exact size, shape, or quantity of particlesnecessary remain unknown. While the clinical relevance of a single smallembolic particle has not been established here, or elsewhere, it isgenerally accepted that, in accordance with minimizing periproceduralpatient risk, reducing the amount and size of particles on or in acatheter or other EP instrument is a common goal shared by all devicemanufacturers. Out of an abundance of caution, to provide a considerablesafety factor for all of our manufactured devices, we have selected 50microns as the clinically relevant particle size to be used to defineacceptance criteria.

This study was designed solely to develop a test method capable ofidentifying catheters with lumens containing unacceptable amounts ofpotentially embolic particles. During this process, it was important toinvestigate the scale and sensitivity of the test instrument, and thenset the test acceptance criteria to an appropriately safe andstatistically justifiable value. Production devices will encounter thesame conservative test as part of an in-process inspection step,rejecting any that are tested to or below the acceptance criteria of109.22.

Results from a previous study showed that this system is also capable ofidentifying devices occluded by single larger (200 micron) particle,with flow readings near 104 sccm. Additional confidence in this testmethod is provided by the fact that those flow values are only slightlylower than that achieved by devices occluded by 50 micron particles.Devices containing single (or multiple) larger particles would also berejected by our acceptance criteria developed from the 50 micronparticle data.

Full validation of the test conditions and acceptance criteria will becompleted using a statistically significant sample set. A Nested GageR&R will be performed by multiple independent operators using devicesoccluded in a consistent manner, validating the test program definedherein. This validation will be executed and reported prior to thesubmission for 510(k) approval of the PentaRay catheter, and a similartest method and subsequent validation developed and implemented duringthe investigation of other catheters containing microlumens.

Example 2. Occlusion Testing Criteria for Reprocessed Abbott (St. JudeMedical) Advisor HD Grid Mapping Catheters

Occlusion testing acceptance criteria were defined for reprocessedAbbott (St. Jude Medical) Advisor HD Grid mapping catheters using theCTS Sentinel Blackbelt (CTS) tester. Specifications of the device areshown in Table 2.

TABLE 2 Usable Item Length French Spacing System Number Description (cm)Size Curve (mm) Electrodes Compatibility D-AVHD- Reprocessed 110 8F DF 316 EnSite Velocity DF16 Advisor HD and Grid EnSite Precision MappingCardiac Mapping Catheter, Systems Sensor Enabled

The CTS Sentinel Blackbelt Mass Flow Tester conducts leak and occlusiontesting of small lumens. During mass flow testing, a device is initiallycharged to a set pressure and then the flow required to maintain thatpressure is reported. Differences in this flow between the same type ofdevice reflect restrictions in the lumen caused by occlusions, or otherdefects, that may negatively impact use of the device and may presentpotential patient risk. Flow-through devices of a different design ormanufacturer may vary. However, provided the unimpeded flow of anysubject device is within the performance range of the test system, thesystem can be adapted for inline inspection of production devices.

Per FDA recommendation, acceptance criteria required the identificationof a single 50 um particle residing within the lumen of a reprocesseddevice and subsequent rejection of any device tested to retain suchocclusions. Equipment capability, sensitivity, and test parameters wereestablished in Example 1. The results of particulate identificationtesting, including the full test method validation, were recorded inExample 4.

The Advisor HD Grid and PentaRay share similar design characteristics.Both devices contain a polyimide microlumen (FIG. 7) that runs fromproximal sideport tubing at the handle through the shaft exiting at thedistal tip (FIG. 8). The Advisor HD Grid has a slightly larger lumendiameter (0.018″ I.D.) than the PentaRay (0.012″ I.D.), and the PentRayhas a slightly longer usable length (115 cm) versus the Advisor HD Grid(110 cm). The Advisor HD Grid also has a perforated cap over the lumenat the distal tip, whereas the PentaRay terminates in an open lumen. Allof these properties affect the flow rate necessary to maintain the setpressure, which is why characterization of a subject device is requiredin the development of device-specific test acceptance criteria.

Understanding that flow characteristics are unique to each device, thedata from the study conducted herein will be used to define acceptancecriteria for the Advisor HD Grid.

Flow Characterization and Occlusion.

Samples selected included sixty-eight (68) clinically-used andreprocessed devices and two (2) original manufacturer (OM) devices. Onthe CTS system, using a new program with no acceptance criteria, initialcharacterization of the two OM and fifty-eight of the reprocesseddevices was performed to assess the non-occluded flow rate. Fifty-eightreprocessed devices were then prepared, inoculating a single 50 μm beadinto the lumen at the proximal end and then incubated a minimum of 48hours at 65° C. prior to testing (to ensure the evaporation of the beadbuffer solution which might otherwise affect test results).

Ten (10) reprocessed devices were inoculated with the bead buffersolution alone (no particulate) to serve as carrier controls. Followingincubation, the devices were analyzed on the CTS, recording a singleflow measurement for each sample.

Results are shown in FIGS. 9A-C to FIG. 13. Data was analyzed in Minitab18. At 95/95 confidence, the upper bound of the probability plot for thedevices containing a particulate defines the acceptance criteria.

Therefore, acceptance criteria for the Advisor HD Grid device is 157.32sccm. Advisor HD Grid devices that test at or below these measurementswill FAIL. Devices that test above these measurements will PASS.

Example 3. Occlusion Testing Acceptance Criteria for Reprocessed St.Jude Medical BRK Transseptal Needles Using the CTS Sentinel Blackbelt(CTS) Tester

Specifications of the device are shown in Table 3

TABLE 3 OEM Needle Usable Product Gauge Bevel Curve Length OEM ProductDevice Code Size Angle Type (cm) St. Jude Transseptal 407200 18 ga 50⁰BRK 71 Medical BRK Needle 407201 BRK-1 71 Transseptal 407205 BRK 89Needles G407215 BRK-1 89 407206 BRK 98 407207 BRK-1 98 St. Jude G40720830⁰ BRK XS 71 Medical BRK G407209 BRK-1 XS 71 XS G407210 BRK XS 89Transseptal G407216 BRK-1 XS 89 Needles G407211 BRK XS 98 G407212 BRK-1XS 98

Devices were reprocessed and inoculated with a single 50 μm bead intothe lumen of OM and clinically-used, reprocessed devices. Devices wereincubated a minimum of 48 hours at 65° C. prior to testing. On the CTSsystem, using a new program with no acceptance criteria, initialcharacterization of an OM, non-occluded device was conducted toestablish the flow rate range for both 71 and 98 cm devices. Challengeddevices were then analyzed and 5 measurements recorded for each sample.Each sample was tested five (5) times. The number of unique samplestested can be calculated by dividing the data points (N) shown by five(5). Data was analyzed in Minitab 18. A95/90 Confidence Interval is usedto define the acceptance criteria for each needle. Results are shown inFIGS. 14A-C to FIG. 18.

Test program acceptance criteria is unique to the length of the needle,and is defined as shown in Table 4.

TABLE 4 Needle size (cm) Flow rate acceptance criteria (sccm) 71 175.889 161.1 98 154.3

Respective devices that test at or below these measurements will FAIL.Devices that test above these measurements will PASS.

Example 4. Detecting a Single 50 Um Particle in Small Lumens

The purpose of this report is to provide documented evidence that theCTS Sentinel Blackbelt (CTS) tester using the small lumen occlusion testmethod and parameters defined in Example 1 is capable of reliablydetecting a single 50 um occlusion in small lumens (similar to thosefound in the PentaRay family of products).

The study used the following subject device:

TABLE 5 Device Scope Original Manufacturer (OM): Biosense Webster OMDescription: PentaRay Nay eco High-Density Mapping Catheter OM ItemNumber(s): See Table 6 below. Device Used: D128207, D128208, D128210,D128211

TABLE 6 Item Numbers Usable Item Length French Spacing Elec- NumberDescription (cm) Size Curve (mm) trodes D128207 PentaRay Nav 115 7F F4-4-4 20 eco High-Density D128208 PentaRay Nav 115 7F F 2-6-2 20 ecoHigh-Density D128210 PentaRay Nav 115 7F D 4-4-4 20 eco High-DensityD128211 PentaRay Nav 115 7F D 2-6-2 20 eco High-DensityEquipment List (as Below or Equivalent/Similar)

-   -   6.1 1 ml 28G×1/2″ disposable syringe (Ser. No. 10/049,962)    -   6.2 50 ml Conical (43237-2)    -   6.3 Bangs Bead Solution with 0.1% surfactant (SOLN1)    -   6.4 Polyvinylpyrrolidone (PVP40-50G)    -   6.5 50 um Particle Size-Standard Solution (64190-15)    -   6.6 4-2500× Compound Microscope (B120C-E1)    -   6.7 1.3MP Digital Camera (MD130)    -   6.8 0-6× Celestron Microscope (44308)    -   6.9 Particle Trap Plates    -   6.10 Single Channel Pipettors & Disposable Tips    -   6.11 CTS Sentinel Blackbelt with Mass Flow Sensor    -   6.12 PentaRay Occlusion Test Fixture (T-0056)        Sample Device Collection and Processing:

Devices that were used for this study include sixty-eight (68)clinically used (natively soiled) reprocessed PentaRay devices receivedfrom various collection sites covering all item numbers listing in thescope (Table 5). Twenty-Nine (29) devices were inoculated with a single50 um particle as described in Example 1. Twenty-Nine (29) devices wereleft unchallenged following reprocessing. The remaining ten (10) deviceswere challenged with bead buffer alone (SHAM).

A test fixture (T-0056; FIG. 19) was utilized to straighten each deviceshaft during testing, reducing variability introduced by randompositioning. The distal tip of the device was shielded with anopen-bottom conical tube positioned against the particle trap plate,which allowed the recovery of a particle exhausted from the lumen duringtesting.

Inoculation, syringe, and lumen flushing images were recorded using4-2500× magnification on an AmScope microscope fitted with a 1.3MPdigital zoom capable camera. Particle traps were analyzed and imagesrecorded using 0-60× magnification provided by a Celestron microscope.

Acceptance Criteria:

TEST PROGRAM acceptance criteria is defined to be 109.22 (Standard CubicCentimeters per Minute) sccm, as documented in Example 1.

Mass Flow>109.22 sccm=PASS

Mass Flow≤109.22 sccm=FAIL

Known Good devices PASS, known bad devices (challenged with a single 50μm particle) FAIL, and the study shall achieve 95/90 confidence.

Deviation:

Data was analyzed in Minitab 18 to 95% confidence.

Results:

Results are shown in FIG. 20 to FIG. 24.

Discussion

As observed in the interval plot (FIG. 20), all mass flow data for theunchallenged reprocessed samples and sham control sets are above thetest acceptance limit, while the challenged device data points are wellbelow the acceptance limit. There was no statistically significantdifference between mass flow readings among the unchallenged reprocessedand sham (challenged with bead buffer alone) sample sets (FIG. 21).However, there was a remarkable difference between unchallengedreprocessed and challenged sample sets (FIG. 22).

The 95%/90% upper bound of the probability plot for the challengeddevice data recommends a test acceptance limit of 107.66 sccm (FIG. 23).Retaining the 109.22 sccm test limit defined during test methoddevelopment exceeds 95%/98% (FIG. 24). This further suggests that thedefined test acceptance limit is quite conservative and includes aconsiderable safety factor.

Magnified images taken both prior to and following inoculation andtesting (Example in FIG. 25) provide evidence that test conditionsinvolved a single particle inoculated within the lumen of challengeddevices. It is of interest that devices that exhausted the particleduring testing (where the particle was observed in the particle trapfollowing testing) experienced a measurably higher flow rate than thosethat retained the particle (as evidenced by the absence of a particle onthe particle trap, but its presence in the lumen flush fluid). Theobjective of this study was to develop an inline inspection test capableof detecting and rejecting devices that contain a single 50 um particlewithin the lumen of a reprocessed device.

CONCLUSION

This study was conducted at a 95%/90% confidence interval to validatethe acceptance criterion for the small lumen occlusion test. Thisconfidence interval required 29 of 29 challenged samples to FAIL (readat or lower than 109.22 sccm) and 29 of 29 unchallenged reprocessedsamples to PASS (read higher than 109.22 sccm). This was achieved,signifying that the CTS mass flow tester is capable of reliablydetecting occlusions as small as a single 50 um particle in lumens ofreprocessed subject devices. It also confirms that this test program iscapable of reliably rejecting devices that contain such occlusions.

REFERENCES

-   1. Horowitz, L. N.; Kay, H. R.; Kutalek, S. P.; Discigil, K. F.;    Webb, C. R.; Greenspan, A. M.; Spielman, S. R. Journal of the    American College of Cardiology 1987, 9 (6), 1261-1268.-   2. Haghjoo, M.; Vasheghani-Farahani, A.; Shafiee, A.; Akbarzadeh,    M.; Bahrololoumi-Bafruee, N.; Alizadeh-Diz, A.; Emkanjoo, Z.;    Fazelifar, A.; Bakhshandeh, H. Research in Cardiovascular Medicine    2018, 7 (1), 20.-   3. Electrophysiological Studies. Hopkins medicine test_procedures    cardiovascular electrophysiologic al_studies_92, p07971 (accessed    Dec. 18, 2018).-   4. USP<788> PARTICULATE MATTER IN INJECTIONS, The United States    Pharmacopeial Convention, 2018-   5. Langille, S. PDA Journal of Pharmaceutical Science and Technology    2013, 67, 186-200.-   6. Puntis, J.; Wilkins, K.; Ball, P.; Rushton, D.; Booth, I.    Archives of Disease in Childhood 1992, 67, 1475-1477.-   7. Mettler, F.; Guiberteau, M. Essentials of nuclear medicine    imaging; Elsevier Saunders: Philadelphia, 2012.-   8. AAMI TIR42:2010, Evaluation of Particulates Associated With    Vascular Medical Devices-   9. Food and Drug Administration (FDA). Coronary, Peripheral, and    Neurovascular Guidewires—Performance Tests and Recommended    Labeleing; 2018.-   10. Haines, D.; Stewart, M.; Ahlberg, S.; Barka, N.; Condie, C.;    Fiedler, G.; Kirchhof, N.; Halimi, F.; Deneke, T. Circulation:    Arrhythmia and Electrophysiology 2013, 6, 16-22.-   11. Haines, D.; Stewart, M.; Barka, N.; Kirchhof, N.; Lentz, L.;    Reinking, N.; Urban, J.; Halimi, F.; Deneke, T.; Kanal, E.    Circulation: Arrhythmia and Electrophysiology 2013, 6, 23-30.-   12. Rapp, J.; Pan, X.; Sharp, F.; Shah, D.; Wille, G.; Velez, P.;    Troyer, A.; Higashida, R.; Saloner, D. Journal of Vascular Surgery    2000, 32, 68-76.-   13. Reina-De La Torre, F.; Rodriguez-Baeza, A.;    Sahuquillo-Barris, J. The Anatomical Record 1998, 251, 87-96.

What is claimed is:
 1. A method of determining acceptance criteria foridentification of an occluding particle in a lumen of a device to beinspected, the method comprising: a. isolating a defined number of oneor more occluding test particles; b. occluding the lumen of arepresentative device with the defined number of particles by adheringthe particles in the lumen of the representative device; c. obtaining amass flow measurement for the occluded representative device; and d.calculating an upper test limit mass flow rate for the occludedrepresentative device; wherein the upper test limit mass flow rate isthe acceptance criteria, and wherein an inspected device is determinedto be occluded if a mass flow measurement for the inspected device isequal to or lower than the acceptance criteria, and the inspected deviceis determined to be unoccluded if the mass flow measurement in theinspected device is higher than the acceptance criteria.
 2. The methodof claim 1, wherein the device is a electrophysiology medical device. 3.The method of claim 1, wherein the lumen of more than one representativedevice is occluded, and wherein the upper test limit mass flow rate isan upper boundary of a probability plot at 95/85 confidence interval orhigher.
 4. The method of claim 1, wherein isolating a defined number ofparticles comprises: a. suspending particles in a bead solutioncomprising a surfactant and aqueous polymeric adhesive; and b. isolatingone or more single particles under magnification into a bead solution.5. The method of claim 4, wherein a single particle is isolated.
 6. Themethod of claim 4, wherein the bead solution is a buffered bead solutioncomprising less than about 0.2% aqueous polymeric adhesive and less than0.5% surfactant.
 7. The method of claim 1, wherein adhering theparticles in the lumen of the representative device comprises: a.injecting the particle into the lumen of the representative device; andb. drying the lumen.
 8. The method of claim 7, wherein the lumen isdried by incubating the device in a recirculating air oven for about 48hours at about 65° C.
 9. The method of claim 1, wherein obtaining a massflow measurement for the representative device comprises: a. chargingthe lumen with air to a predetermined pressure; and b. measuring theflow of air sufficient to maintain the pressure over a preset period oftime to obtain the mass flow measurement.
 10. The method of claim 9,wherein the mass flow measurement is obtained using a mass flowmeasurement instrument.
 11. The method of claim 1, wherein therepresentative device is occluded with one occluding particle.
 12. Themethod of claim 1, wherein the representative device is occluded with a50 microns NIST traceable particle size standard polystyrene beads. 13.An inspection method for identification of an occluding particle in alumen of a device to be inspected, the method comprising: a. obtaining amass flow measurement of the device; b. comparing the mass flowmeasurement to acceptance criteria obtained for a representative device,wherein the acceptance criteria are determined by: i. isolating adefined number of one or more occluding test particles; ii. occludingthe lumen of a representative device with the defined number ofparticles by adhering the particles in the lumen of the representativedevice; iii. obtaining a mass flow measurement for the occludedrepresentative device; and iv. calculating an upper test limit mass flowrate for the occluded representative device; wherein the upper testlimit mass flow rate is the acceptance criteria, and the inspecteddevice is determined to be occluded if the mass flow measurement in theinspected device is equal to or lower than the acceptance criteria, andthe inspected device is determined to be unoccluded if the mass flowmeasurement in the inspected device is higher than the acceptancecriteria.
 14. A system for determining acceptance criteria for a deviceto be inspected for the presence of an occluding particle in a lumen ofthe device, the system comprising: a. a mass flow measurement instrumentfor obtaining a mass flow measurement of a representative device; b. acomputer system having at least one processor and associated memorycomprising instructions for calculating an upper test limit mass flowrate for an occluded representative device and instructions which, whenexecuted by at least one processor, cause the at least one processor to:i. receive a mass flow measurement of the occluded representativedevice; ii. calculate an upper test limit mass flow rate for theoccluded representative device; and iii. output the upper test limitmass flow, wherein the upper test limit mass flow rate is the acceptancecriteria, and wherein an inspected device is determined to be occludedif a mass flow measurement in an inspected device is equal to or lowerthan the acceptance criteria, and the inspected device is determined tobe unoccluded if the mass flow measurement in the inspected device ishigher than the acceptance criteria.